Spontaneous mutations that affect the cerebral vasculature provide insights into the molecular mechanisms underlying its development, structure, and integrity. The genes responsible for mutations with highly penetrant phenotypes can be efficiently identified when they arise in genetically tractable animal models such as mice. Furthermore, animal models provide a valuable resource for in vivo studies pertaining to human disease. However, mouse models affecting the cerebral vasculature are lacking. A spontaneous mouse mutation has been identified that shows adult onset, bilateral, progressive degeneration in the brain. Histological analysis shows complete vacuolization of the tissue in affected mice, consistent with cerebral ischemia. The mutation is therefore called Cerebral Ischemic Damage (cid). Pathology always begins in the ventral temporal cortex and progresses to the ventral hippocampus and eventually the dorsal cortex. Importantly, preliminary studies are inconsistent with typical infarct mechanisms such as thrombosis, embolism, aneurism, or circulatory insufficiency. Furthermore, the brain is the only tissue affected. The phenotype therefore appears most consistent with a defect intrinsic to the cerebral vasculature. The mutation arose in a C57BL/6 genetic background and maps to a 9 cM interval on mouse chromosome 9. The goal of the proposed research is to further characterize the phenotype of the cid/cid mice and to identify the genetic lesion responsible. Additional phenotypic characterization will definitively determine the onset and progression of the cerebral degeneration. Furthermore, more detailed analysis of the pathology will identify possible cellular mechanisms of the degeneration. How the vasculature becomes functionally compromised is also unclear. For instance, does the pathology result from defects in blood-brain-barrier permeability or from a failure to maintain adequate blood perfusion in the tissue? Therefore, functional tests of the cerebral vasculature will be performed. Understanding the molecular basis for the disease requires the identification of the gene responsible. Genetic and molecular analyses toward this end are underway. As the genetic interval on chromosome 9 narrows, molecular analysis of candidate genes in the region will begin. The genetic, molecular, and phenotypic characterization of the cid mice will greatly enhance our understanding of the biology of the cerebral vasculature.